A Randomized Phase II Study of Two Schedules of Bryostatin-1 (NSC339555) in Patients with Advanced Malignant Melanoma – A National Cancer Institute of Canada Clinical Trials Group Study

Purpose: This study addressed theefficacy and toxicity of the novel compoundBryostatin-1 (NSC 339555), a novel agentwith antineoplastic, hematopoietic andimmunomodulatory activity in a variety ofin vitro and in vivo systems.Patients and methods: This phase IIstudy randomly assignedchemotherapy-naïve patients withuntreated metastatic melanoma andmeasurable disease to two schedules oftreatment: Arm A, 25 μg/m2bryostatin-1 given as a 24 hour continuousinfusion weekly or Arm B,120 μg/m2 bryostatin-1 given as a72 hour continuous infusion every 2 weeks.Although objective response was assessedusing standard NCIC CTG criteria,antitumour activity was assessed using amultivariate endpoint incorporating bothresponse (CR and PR) and early progression(PD at ≤ 8 weeks). Seventeen patientswere randomized to each arm.Results: Arm A was better tolerated with 86.7% of15 evaluable patients receiving ≥ 90%of planned dose intensity versus 76.5% of17 evaluable patients in Arm B. On Arm B,three patients experienced serious adverseevents and three patients had to be removedfrom protocol therapy due to toxicity. Themost common side effect was myalgia (33%grade 1–2 on Arm A versus 65% on Arm Bwith 5 patients experiencing grade 3 andone patient grade 4). Lethargy was morecommon on Arm A but more severe on Arm B. Other side effects such as nausea, diarrheaand headache were generally mild tomoderate in nature and occurred with asimilar frequency on both arms. Hematologicand biochemical toxicity were minimal. This trial was closed early because theprotocol-stopping rule was met based onlack of required responses and on thenumber of early progressions on both arms.No partial or complete responses were seen;3 patients randomized to Arm A had stabledisease (duration 9–24 weeks) as did 4patients (duration 10–38 weeks) randomizedto Arm B.Conclusion: Arm A wasbetter tolerated than Arm B. We concludethat bryostatin-1 has little efficacy inthe treatment of metastatic melanoma witheither of the schedules studied.